1. Filed of the Invention;
The present invention relates to a material used for diagnosis by nuclear magnetic resonance imaging, and particularly to a material which may be used for the preparation of models equivalent to living tissue, such as simulating images, phantoms or reference materials, required in maintenance, inspection, servicing and appraisal of a system used for diagnosis by nuclear magnetic resonance (NMR) imaging and required also in analysis and study of the images obtained by the NMR diagnosis It will be noted here that the expression "diagnosis by nuclear magnetic resonance" or "NMR diagnosis" used throughout the specification and appended claims means the diagnosis of a certain diseased site by the analysis of the NMR image of the diseased site. The material provided by the present invention may also be used for the preparation of a skin marker which is applied on a certain position of the patient body in the practice of NMR tomography wherein the location of the diseased site should be determined , while a certain point or position of the surface of the patient body is taken as a reference location, prior to the commencement of the radiotherapy or surgical treatment.
2. Related Art Statement
The method for the diagnosis of an internal site, for instance, to have an information concerning a certain diseased site or a condition of blood stream, is generally referred to as the NMR image diagnosis method, the NMR tomographical diagnosis method, the NMR imaging method, MRI (magnetic resonance imaging) method, the MMR (medical magnetic resonance) method, the MNI (multi-nuclear imaging) method and he NMR-CT (computerized or computer assisted tomography) method. In such a method, a living body is placed in a static magnetic field and applied with a radio-frequency wave (having a high frequency) corresponding to the resonance wave length with the atomic nucleus of hydrogen or proton to excite protons in the living tissue, and then the magnetic information generated from the thus excited atomic nuclei are detected as the output signals to form an image by such output information. Such an image includes the nuclear magnetic information concerning the concentration of protons contained in the living tissue (which gives an information concerning the water content in the living tissue), those concerning the spin-lattice (longitudinal) relaxation time (T.sub.1) and those concerning the spin-spin (transverse) relaxation time (T.sub.2). By analysing the image, the condition of the diseased site may be distinguished, and the distribution of the blood stream velocity in the living tissue may be imaged. The NMR imaging method is expected as a novel tool for the early stage diagnosis of a variety of diseases, since it is superior over or overcoming the demerits of the known X-ray tomography, DSA (digital substraction angiography), PET or PE-CT (positron emission tomography) and US (ultrasonic method) for the reasons that any desired cross section of a living tissue can be imaged without trepassing internally of the living tissue, without being disturbed by the bones or air in the respiratory organs, and without any apprehension of exposure by a radioactive isotope or X-ray. However, the conventional system used for the NMR diagnosis is inferior in operational stability when compared with the stabilities of the systems used for the X-ray-CT and PE-CT methods. (In this connection, reference should be made to Hiroki Kawaguchi, "SHIMAZU HYORON", 41, 137 (1984).) In practice of the NMR imaging, the system used therefor must always be paid with continuous care as to its maintenance, inspection, servicing, adjustment and appraisal of the performance characteristics.
In general, the device for reading out an information and the display device incorporated in the NMR system are computerized, and it has been pointed out that "there is a grave tendency that exceedingly many chemists apt to accept the displayed data as accurate analytical results without taking what has been done in the system into account." In the NMR system for diagnosis, the control system, the manual for operations and the mode of imaging have not been standardized, often leading to difficulty in study and analysis of the image. Under such circumstances, certain erroneous diagnoses have been specifically pointed out and there is earnest demand for the search and establishment of a standard probe used for inspecting the operational condition of the system (E. L.. Madsen, "Mag. Res. Imag.", 1, 135 (1982)).
It is desired that an NMR system should be placed at a location in a building constructed of wooden and plastics materials and isolated from the hospital, ideally pipes for city water, gases and drainage conduits being made of non-magnetic materials, such as synthetic resins, and a fluorescence lamp should not be used in the building. In the general practical application, such systems are installed within hospital buildings while being shielded from the neighbouring magnetic materials. However, it is necessary that the system should be separated by a distance of more than 10 meters from an elevator, roadway, underground railway and similar equipment, and it is also necessary that all of the neighbouring magnetic wave generating sources including television, magnetic tapes and electric lead cables should be shielded. However, there is often a case where such necessary condition is not satisfied. It will thus be understood that the operational conditions for satisfactory functional effect of the NMR system depends seriously on the maintenance, control and adjustemnt thereof, so that the adverse influences by the iron base materials in the building structure and/or surrounding substances should be amended by the provision of a symmetrical coil. However, significant difficulties are encountered in amendment of the influences due to magnetic field established by radio frequency waves or plate-shape magnetic wave sources. In addition, since the system cannot be assembled pecisely in accordance with the theory and design thereof, similarly to general precise mechanical instruments, it is frequently pointed out the uneven orientation of the static magnetic field in the transverse direction, and it is hard to amend such an uneven orientation of the magnetic field. Although it is convenient from the economical standpoint of view to lessen the magnetic field, in order to improve the uniformity of the static magnetic field, in order to improve the uniformity of the static magnetic field, it is meaningless to provide an NMR system for handling a small sample or test specimen when it is intended that the system is used for the diagnosis of a human body. It should be appreciated that a large scale magnet used for the diagnosis of a human body is accompanied with various imperfections which are not corrected or amended to give satisfactory data since no standard therefor has not yet been established at the present day.
In operation of the system, there are many problems which should be born in mind of the operator or the analyst. For example, the level of the radio frequency wave and the pulse interval should be properly selected, and the scanning speed should be pertinently set not to reduce the resolution power of the system, depending on the conditions of the disease. Furthermore, the NMR signals depend on the specific type of system used and on the intensity of the static magnetic field, and the conversion factor between different systems can not be determined monistically, as reported by I. Young, "Electronics & Power", 1984, March, 205. Moreover, even when the same system is used, the T.sub.1 and T.sub.2 (image signals) vary in response to the pulse interval (T.sub.r), the delay time (T.sub.d) and the echo time (T.sub.e). However, the photographing condition for imaging cannot be set monistically to a certain condition. In detail, the difference (i.e. the contrast between the image of normal tissue and that of diseased site) in the NMR signal induced by the change due to a morbid state is to be discriminated by the NMR diagnosis. However, since more than an hour is expended for individual imaging by calculation of the NMR signals (proton density.rho., T.sub.2) and special value can not always be expected by such individual imaging, it is a common practice to form an image including all of the above factors as a prompt measure. In such a case, rather than taking the aforementioned three factors equally into account, the endeavor is directed to the establishment of an image having clear contrast so as to have the maximum discremination ability for discriminating the diseased site by imaging the respective factors through the non-uniformly weighed addition (while adopting the trial-and-error method) in response to the condition of disease, the personal difference and the conditions of the surrounding tissues around the diseased site. (In this connection, reference should be made to G. Hansen et al., "Radiology", 136, 695 (1980); I. E. Crooks, "I.E.E.E. Trans. Nucl. Sci.", NS-27, 1239 (1980).) For these reasons, unitary display of the NMR signals is sacrificed to result in devoid of interchangeability between the images to induce problems in analysis of the images inevitably.
In consideration of the aforementioned status quo of the NMR imaging technology, it is a natural demand for a reference or control specimen for the objective appraisal, judgement on the maintenance, control, adjustment operational and performance conditions and for the analysis of the formed images. Examples of the materials which have been already proposed as those which maybbe used for the preparation of reference specimen in the NMR imaging method, include tetramethylsilane, hexamethyldisiloxane, hexamethyldisilane, neopentane, DSS (sodium 2,2-dimethyl-2-silapentano-5-sulfonate) and sodium 2,3-tetradeuterium-3-trimethylsilylpropionate. Although these materials are conveniently used in the chemical analysis as the materials for preparing reference specimens used to measure the chemical shifts of the NMR informations, they are not suited for use as the materials for the reference specimen used to provide basic informations or factors (proton density.rho., T.sub.1 and T.sub.2) in the NMR diagnosis, at all.
In some cases, polymethyl methacrylate and a low density polyethylene have been used in an NMR system for the adjustment purpose. However, the polymethyl methacrylate is used merely for the inspection of the peak width of the chemical shift during the chemical analysis and the low density polyethylene is used only for the adjustment of the level of radio frequency wave. The both materials have no utility as the reference materials used for the adjustment operation when the system is used for obtaining NMR informations concerning a living body.
It has been proposed to use water, an aqueous solution of manganese sulfate, nickel chloride or copper chloride, and sulfuric acid, as the standard for inspection and adjustment of the system, since the NMR diagnosis is applied for the diagnosis of a substance (i.e. a living tissue) containing a large quantity of water. However, water is improper for a standard in the NMR analysis at all, since it is seriously affected by the changes in test conditions, such as temperature, trace amounts of impurities, e.g. dissolved oxygen, iron or nickel. On the other hand, it is extremely difficult to prepare a solution simulating NMR informations of a living tissue (water content, T.sub.1 and T.sub.2) by the use of any of the aforementioned solutions.
There are known in the art a variety of solids (gels) containing water and having a construction resembling living tissues, the examples being gelatin, agar, polyacrylamide, carrageenan, agarose, jam, boiled egg, KONNYAKU (devil's tongue), alginic acid gel and bean-curd. However, a material having a water content agreed with that of the internal organs of a living body (namely, having a water content of from about 70 to 85 wt. %) and having the T.sub.1 and T.sub.2 values agreed with those of the internal organs of a living body has not yet been known. Although continuous attempts are made to improve the process for the preparation of these hydrogels so as to bring the NMR signals .rho., T.sub.1, T.sub.2) thereof close to those of the living tissues by admixing some quantities of impurities, such attempts have not succeeded as will be described hereinbelow. It is also required that such a material must be suited for the provision of a living tissue model (phantom) having good performance characteristics, shape-retaining property or satisfactory moldability for simulating internal organs. However, a material satisfying all of the requirements, as mentioned above, has not yet been offered. For instance, a gelatin containing more than 70% of water is too weak and apt to be broken, and a gelatin containing 60 to 70% of water has an excessively high T.sub.1 and T.sub.2 values as compared to those of the living tissues. Chemical treatment of gelatin has been studied to eliminate the tendency of fluidization thereof at the room temperature and to improve the T.sub.1 and T.sub.2 values thereof. However, such efforts produced no valuable fruit, since there appeared uneven gelation during the step of cross-linking and solidifying the gelatin. Anyway, it is not expectable to bring the three factors, i.e the water content (70 to 85%), T.sub.1 and T.sub.2, close to those of the living tissues by the use of any gelatin composition. Although a polyacrylamide gel having a water content ranging from 70 to 85% may be prepared, such a gel has an exceedingly high T.sub.2 value and is apt to lose uniform structure during the cross-linking polymerization (gelation) step. Further disadvantages of such a polyacrylamide gel are that the gel per se is too fragile to be easily broken and that the NMR signals vary with the lapse of time.
Other known materials include bean-curd, carrageenan, alginic acid, agar, agarose, boiled egg, poly(2-hydroxyethyl methacrylate) gel, Curdlan (I. Maeda et al., "Agr. Biol. Chem.", 31, 1184 (1967)), carboxymethyl cellulose (CMC), acrylonitrile-stach graft gel (E. B. Bagley et al., "Ind. Eng. Chem. Prod. Res. Dev.", 14, 105 (1975)), xanthane gum, Locust Bean Gum, tragacanth gum, furcellaran, methyl cellulose, casein, albumin, fucoidin, triethanolamine alginate, tamarind gum, karaya gum, gatti gum and jam (such as pectin gel). However, all of these materials are too weak as the materials used for constructing models, and in addition water content of each of these materials is limited so that both of T.sub.1 and T.sub.2 thereof cannot be agreed with those of living tissues. Although the KONNYAKU and poly(N-vinylpyrrolidone) have tentatively satisfactory shape-retaining property and moldability, the water content of the former is too large with extremely high T.sub.1 and T.sub.2 values, and the latter has an adequate water content but is too high in T.sub.1 and T.sub.2 values. Even if an adjusting agent, such as nickel, manganese, copper or graphite, is added to poly(N-vinylpyrrolidone), both of the T.sub.1 and T.sub.2 values thereof cannot be brought to the values equivalent to those of living tissues.
Because of the fact that any of the known materials (chemical substances) have many demerits, as described above, a fresh tissue of an animal has been used reluctantly as the control material in practice. However, such an animal-originated material is deteriorated significantly with the lapse of time even when stored in a cold place, as reported by R. V. Damadian, U.S. Pat. No. 3,789,832 (1974), and significant differences are found between the samples picked up from individual animals of the same species. Under such circumstances, it should be reasonable and well-grounded to accept the opinion, which has been repeatedly pointed out, for example, by E. L. Madsen, "Mag. Res. Imag.", 1, 135 (1982), that it is necessary to find out a water-containing material (for phantom) which is not originated from a living body (namely a chemical substance) and repeatedly usable for a long time while having substantially equivalent NMR informations (.rho., T.sub.1, T.sub.2) and being improved in shape-retaining property and satisfactory moldability.
It is also necessary to learn the precise steriographical position of a certain diseased site or to learn the precise distance from certain standard locations on the surface of a patient body prior to trepass internally of the patient for the purpose of examination or medical treatment, in order to increase the effect of surgical treatment and to minimize damages of normal tissues surrounding the diseased site by the surgical treatment. One example of such diagnosis methods is the so-called NMR-CT method (nuclear magnetic resonance crosssectional tomography). Although many internal organs and various diseased sites may be clearly displayed by the NMR-CT method without trepassing internally of the living body, the locations thereof, particularly the relative positioning or distance of each diseased site from a ceratin location on the surface of the patient body, are not clarified by the NMR-CT method.
In a medical treatment by radiography or various surgical operations or treatments, the living tissue at a certain diseased site in a living body is intended to be destroyed or resected through another specific position on the surface or skin of the body, and thus it is essential to learn the precise interrelation between the specific position on the skin and the certain diseased site internally of the living body by preliminary measurement.
In a case where a diseased site, such as hematoma or tumour, is occasionally present on the skin surface, both of the disease on the skin and the diseased site within the living body can be imaged clearly and concurrently. However, such a case is rare and unexpectable.
It is, therefore, the most convenient measure to apply some substance which emits a clear NMR signal different from the signal emitted from a normal skin tissue on a certain location of the skin (on a normal skin of the living body) across the cross section of the diseased site within the body, whereby the specific location on the surface of the body is imaged on the NMR cross sectional picture together with the image of the diseased site in the body. However, it is not easy to provide a substance (such a substance being referred to as "skin marker" in the art) which always satisfies the aforementioned requirement under the operation condition (within the range of operation) for the NMR diagnosis. Water (pure water) is the first substance which should be called to mind as a material suitably used for this purpose. Pure water emits a more intensive proton signal as compared with that emitted from the skin which contains 51 to 69% of water, with the longitudinal relaxation times (T.sub.1) and especially transverse relaxation time (T.sub.2) are prolonged, and has an advantage that it is not harmful to the skin. However, pure water has no shape-retaining property when put on the skin. This problem may be tentatively obviated by applying a pouch filled with water on the skin surface. However, it is desirous that a marker having initially an arbitrary shape and dimensions be applied on the surface of the living body, followed by stepwise cutting of the peripheral portions of the marker during the sequential operations of forming cross sectional images thereof together with the formation of images of the diseased site so that the shape and dimensions of the marker are brought closer to those of the diseased site to form an image of the diseased site (having certain shape and dimensions) on the skin surface. Since the pouch containing water cannot be cut, it does not satisfy such requirement. There have been known some materials which contain large quantities of water to emit NMR signals close to that emitted from water and may be cut to have shapes and dimensions which agree with those of the diseased site, the examples being gels of jelly, jam, agar, carrageenan, carboxymethyl cellulose, polyvinyl alcohol complexes of boric acid, bean-curd, alginic acid, agarose, curdlan, acrylonitrile-starch graft polymer, xanthane gum, Locust Bean gum, tragacanth gum, furcellaran, methyl cellulose, fucoidin, tamarind gum, karaya gum and gatti gum. However, all of these gels are poor in mechanical strength, and some of them have no shape-retaining properties so as to be unsuited for adhesion and fixation on a certain location of the skin surface.
Although a Congo Red complex of polyvinyl alcohol has a high water content and elasticity resembling that of a soft rubber, it is not preferred since it is harmful to living tissues as disclosed by S. Niedermeier, "Graefes Archiv Fur Ophthalmol.", 161 547 (1960), C. L. Schepens et al., "Arch. Ophthalmol.", 64, 868 (1960), W. C. Everett, "Klin. Monatsbl. Augenheilkd.", 141 764 (1962) and Ei Sakaue, "Jap. J. of Clinical Ophthalmology" 18, (1), 7 (1964). The polyacrylamide gel is also harmful to a living body and has another disadvantage that it is mechanically fragile.
KONNYAKU has a shape-retainig property notwithstanding the fact that it contains about 98% of water and emits and NMR signal closely resembling that of water, and may be cut freely. However, KONNYAKU is not suited for rapid and simplified use in response to the need in actual clinical treatment, since it has a problem in storage due to the fact that it tends to be collapsed or fluidized and being suffered from serious syneresis, contraction and deformation unless it is stored while being dipped in a vessel filled with a strong alkali solution (pH 11 to 12) containing an antiseptic agent.